Transcript No Slide Title

Case #1
• 14 yo white male
• Referred after hypercholesterolemia detected on routine
screening because of father’s hypercholesterolemia
• Total cholesterol 290 mg/dl, repeat 286 mg/dl
• Triglycerides 108 mg/dl, HDL cholesterol 55 mg/dl, LDL
cholesterol 209 mg/dl
• Otherwise well/No current medications
• Physical exam, BP WNL, 50th percentile for Ht/Wt
• No xanthelasma, cutaneous xanthomata, or Achille’s tendon
thickening
Case #1
• Activity
– Soccer, swimming, biking
• Diet
– Family already attempting to reduce dietary fat and cholesterol
after learning of elevated cholesterol in patient and father
• Social
– No tobacco/alcohol/substance abuse
– Both parents come with patient to clinic, seem very supportive
Case #1
• Dietary assessment
– 3-day dietary recall to determine average daily intake
• Total calories: 2000 kcal/day
• Composition as % of total calories
– Protein: 22%
– Fat: 28%
» Saturated: 6%
» Monounsaturated: 14%
» Polyunsaturated: 8%
– Carbohydrate: 49%
• Cholesterol content: 221 g/day
• Fiber: 31 g/day
Case #1
53 yo
MI
44 yo
CH 280
69 yo
breast CA
42 yo
CH 310
68 yo
diabetes
hypertension
35 yo
healthy
CH 152
36 yo
healthy
CH 299
6 yo
healthy
CH ?
9 yo
healthy
CH ?
14 yo
healthy
CH 286
66 yo
healthy
Xanthelasma Palpebrarum
Xanthomata Tuberosa
Case #2
• 11 yo white male
• Referred after hypercholesterolemia detected after father
was found to have hypercholestrolemia and recent
myocardial infarction
• Total cholesterol 254 mg/dl, repeat 250 mg/dl
• Triglycerides 102 mg/dl, HDL cholesterol 53 mg/dl, LDL
cholesterol 181 mg/dl
• Otherwise well/No current medications
• Physical exam, BP WNL, 50th percentile for Ht/Wt
• No xanthelasma, cutaneous xanthomata, or Achille’s
tendon thickening
• Activity
Case #2
– Computer games, TV
– Biking
• Diet
– Some meals at home, but often fast food, snacks
– No effort yet to alter diet
• Social
– No tobacco/alcohol/substance abuse
– Parents are separated, lives with mother, who works
two jobs
Case #2
• Dietary assessment
– 3-day dietary recall to determine average daily intake
• Total calories: 2000 kcal/day
• Composition as % of total calories
– Protein: 16%
– Fat: 37%
» Saturated: 17%
» Monounsaturated: 15%
» Polyunsaturated: 5%
– Carbohydrate: 47%
• Cholesterol content: 373 g/day
• Fiber: 13 g/day
Case #2
49 yo
MI
66 yo
healthy
59 yo
hypertension
34 yo
MI
34 yo
CH 159
healthy
36 yo
CH 299
MI 6 mos ago
6 yo
healthy
CH 249
9 yo
healthy
CH 255
11 yo
healthy
CH 250
62 yo
healthy
Risk Factors for Atherosclerotic
Heart Disease
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Hypercholesterolemia
Smoking
Hypertension
Diabetes
Sedentary lifestyle
Male Sex
Family history of CHD
Age (male > 45 yoa, female > 55 yoa)
Evidence Relating Diet, Serum Cholesterol
Level, and Coronary Heart Disease
• Animal studies
• Genetic disorders, such as familial
hypercholesterolemia with elevated serum LDL
cholesterol, are associated with premature
atherosclerosis
• Epidemiologic studies
• Clinical trials
• Autopsy studies
Dietary Saturated Fat and Cholesterol
Intake and Serum Total Cholesterol in
Boys Aged 7-9 Years in Six Countries
Country
Philippines
Saturated Fat
(% of energy)
9.3
Cholesterol
(mg/1000 kcal)
97
Serum Chol
(mg/dl)
147
Italy
10.4
159
159
China
10.5
48
128
U. S.
13.5
151
167
Netherlands
15.1
142
174
Finland
17.7
157
190
Serum Cholesterol in Boys and Middle-Aged
Men and CHD Mortality Rates in Middle-Aged
Men in Industrialized Countries
Serum Total
Cholesterol
(mg/dl)
Boys
Men
CHD Mortality
Per 100,000
Men aged
45-54 years
Portugal
149
203
71
Israel
155
204
119
Italy
159
200
91
Hungary
159
203
276*
U.S.
167
217
170
Netherlands
171
221
134
Poland
176
192
218*
Finland
190
240
264
Country
Coronary Primary Prevention Trial
(CPPT)
• Hypercholesterolemic, middle-aged men
• Treated with cholestyramine
• 19% reduction in fatal and/or non-fatal MI over 7
years
• A 25% reduction in serum cholesterol level
resulted in a 50% reduction in CHD risk
Controlled Angiographic Trials of
Cholesterol Lowering
• Several studies to date in adults
• Regression of lesions in 16-47% with large
decreases in serum LDL cholesterol levels (3448% reduction) for 2-5 years
• Main benefit may be slowing of progression of
atherosclerotic lesions
Why Intervene in Children
• Role of hypercholesterolemia in atherosclerosis well
established in adults
• Children with elevated cholesterol are more likely to have
family members with elevated levels and come from
families with premature atherosclerosis
• Tracking
– Children with elevated serum cholesterol levels are likely to have
hypercholesterolemia later in life
• Autopsy studies
Autopsy Studies
• U.S. soldiers in Korean War (Enos et al, 1955)
– Gross coronary disease in 77% of subjects studied
– Mean age 22 years
– Confirmed in studies from Viet Nam War
• Holman, 1961; Strong and McGill, 1962; Stary, 1989
– Aortic fatty streaks are extensive in childhood
– Coronary fatty streaks appear in adolescence
– Fibrous plaques appear in the second decade with progression
into the second decade
• Bogalusa Study
• PDAY Study
Bogalusa Study
N=93, 2-39 yoa
NEJM 338:1650, 1998
Pathobiological Determinants of
Atherosclerosis in Youth (PDAY)
• Multicenter post-mortem study in 1079 males, 364
females, 15-34 years of age
• Violent death
• Arteries graded for atherosclerotic lesions in aorta
and right coronary artery
• Serum lipoproteins measured
• Serum thiocyanate measured as an index of smoking
Arterioscler Thromb Vasc Biol 17:95, 1997
PDAY Results
• Extent of surface area with fatty streaks and
raised lesions increased with age in all vessels
• Serum VLDL plus LDL cholesterol positively
correlated with extent of fatty streaks and raised
lesions in all vessels
• Serum HDL cholesterol negatively correlated with
extent of fatty streaks and raised lesions in all
vessels
• Smoking associated with more extensive fatty
streaks and raised lesions in aorta
Pediatric Screening Strategies
• Screen no one. Treat everyone with diet.
• Screen only those children with a positive family
history of premature atherosclerotic disease or
known hyperlipidemia.
• Screen all children.
National Cholesterol Education
Program (NCEP) Recommendations
for Pediatric Cholesterol Screening
• Screen after 2 years of age
• All children with first degree relative with
symptoms or diagnosis of atherosclerotic disease,
hyperlipidemia (serum cholesterol > 240 mg/dl),
or sudden cardiac death before 55 years of age
Percentage of Children Aged 0-19 Years Who Would Be
Screened, and Percentage of Those with LDL Cholesterol ≥130
mg/dl Who Would Be Identified, If the Presence of CV Disease or
Various Levels of Elevated Total Cholesterol in at Least One
Parent Is Used to Select Children for Screening
Parental Cholesterol
(mg/dl) Higher Than
Children Who Would
Be Screened (%)
Sensitivity for
Identification of
Children with LDL
Cholesterol ≥130 mg/dl
200
63.5
86.5
220
44.3
63.5
240
25.1
40.5
260
18.3
29.7
280
15.3
28.4
300
13.9
28.4
The Lipid Research Clinics Prevalence Study (N=1042)
What to Measure
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Total cholesterol
Triglycerides
HDL cholesterol
Calculate LDL cholesterol
– LDL cholesterol=total cholesterol-HDL cholesteroltriglycerides/5
– Not accurate if triglycerides > 400 mg/dl
– Some commercial labs now measure LDL cholesterol directly
• Fasting not necessary for cholesterol measurement alone,
but overnight fast is required for profile
Classification of Total and LDL Cholesterol
Levels in Children and Adolescents
Acceptable
Total Cholesterol
(mg/dl)
<170
LDL Cholesterol
(mg/dl)
<110
Borderline
170-199
110-129
High
≥200
≥130
What to do After Screening
• If total cholesterol > 95th %tile (200 mg/dl),
repeat with full profile
• If confirmed, rule out secondary causes
• Screen family members
• Start Phase I diet and risk factor
reduction/prevention
• Follow-up and consider Phase II diet to reduce
LDL cholesterol to below 95th percentile
Borderline Cases
• 70th-90th percentile (170-199 mg/dl)
• Repeat, if average of two still borderline, get
complete analysis
• If LDL cholesterol is borderline, start phase I diet
and risk factor reduction/prevention
• Recheck in 1 year
Abnormalities not detected by a
simple cholesterol measurement
• Hypertriglyceridemia
• Hypoalphalipoproteinemia (low HDL)
• Elevated apolipoprotein B level with normal
LDL-C (excess number of small LDL particles)
• Elevated lipoprotein(a) level
• Elevated homocysteine level
Secondary Causes of Hyperlipidemia
• Endocrine
– Hypothyroidism
– Diabetes mellitus
– Glycogen storage disease
• Pregnancy
• Renal Disease
– Nephrotic syndrome
• Obstructive liver disease
• Drugs
– Corticosteroids, isotretinoin, thiazides, anticonvulsants, bblockers, anabolic steroids, oral contraceptives
Familial Aggregation of
Hyperlipidemia
• Monogenic
– Heterozygous familial hypercholesterolemia
• Mutations in LDL receptor
• 90% will have CHD by 65 yoa
• 4% of all cases of premature CHD
– Familial Combined Hyperlipidemia
• Expression variable (cholesterol and/or triglyceride elevation) and may be
delayed
• 11% of all cases of premature CHD
• Polygenic
– Accounts for majority of cases of premature CHD
– Expression of a number of genes contributing to hypercholesterolemia and
atherosclerosis combined with environmental factors
Dietary Fat in Children and
Adolescents in the United States
• Age 1-19 years-14% of total calories from
saturated fat
• Age 1-11 years-35% of total calories from fat
• Age 12-19 years-36% of total calories from fat
Phase I Diet
•
•
•
•
No more than 30% of total calories from fat
Less than 10% of total calories from saturated fat
Less than 300 mg of cholesterol/day
Total caloric intake appropriate for normal growth
and ideal body weight
Phase II Diet
•
•
•
•
No more than 30% of total calories from fat
Less than 7% of total calories from saturated fat
Less than 200 mg of cholesterol/day
Total caloric intake appropriate for normal growth
and ideal body weight
Criteria for Drug Therapy
In Children and Adolescents
•
•
•
•
10 years of age or older
Adequate trial of dietary therapy (6 mos-1 yr)
LDL cholesterol level ≥ 190 mg/dl
LDL cholesterol level ≥ 160 mg/dl and
–
–
Positive family history of premature CVD
or
2 or more CVD risk factors persisting after vigorous
efforts to control or eliminate these factors
Goals of Drug Therapy
in Children and Adolescents
• Acceptable-LDL cholesterol level < 130 mg/dl
• Ideal-LDL cholesterol level < 110 mg/dl
• Monitor 6 weeks after starting therapy, then every
3 months until maximal effect, then every 6
months
• Monitor compliance, lipids, growth, and
appearance of side effects
Bile Acid Sequestrants
• Cholestyramine (Questran®), Colestipol (Colestid®)
• Only class of drugs approved for use in children to treat
hyperlipidemia
• Bind bile acids and enhance fecal elimination, upregulate hepatic bile acid synthesis from cholesterol, and
thereby up-regulate hepatic LDL receptors
• Will often increase serum triglyceride levels in mixed
hyperlipidemias
• Not absorbed, side effects mainly constipation, bloating
• Can lower fat-soluble vitamin and folate levels, but
usually not important clinically
• Gritty, “sandy” consistency; compliance a real problem
NCEP Treatment Guidelines
for LDL-C Levels for Adults
Definite
Two or
atherosclerotic more other
disease
risk factors
No
No
Initiation
level
(mg/dl)
> 190
Goal
(mg/dl)
< 160
No
Yes
> 160
< 130
Yes
Yes or No
> 130
<100
HMG CoA Reductase Inhibitors
• “Statins”
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Cerivastatin (BaycolR)
Fluvastatin (LescolR)
Atorvastatin (LipitorR)
Lovastatin (MevacorR)
Pravastatin (PravacholR)
Simvastatin (ZocorR)
• Decrease hepatic cholesterol synthesis resulting in
increased hepatic LDL receptors with increased
clearance of plasma LDL particles
HMG CoA Reductase Inhibitors
• Decrease serum LDL cholesterol levels
• Modest increases in serum HDL-C levels
• The more potent statins, atorvastatin, cerivastatin,
and fluvastatin, also significantly decrease
triglyceride levels, possibly serving as effective
monotherapy in mixed hyperlipidemias
HMG CoA Reductase Inhibitors
Adverse Effects
• Myalgias, myopathy, rhabdomyolysis
• Risk of rhabdomyolysis and acute renal failure
especially high with combined therapy with fibric
acid derivatives, niacin, cyclosporine,
erythromycin, and azole antifungals
• Transaminase elevation
• Fetal toxicity
Niacin
• NiaspanR (extended release tablets)
– If equivalent dose of crystalline niacin is substituted,
toxicity will result, and fulminant liver failure has
been reported
• Decreases total cholesterol, LDL-C, and
triglycerides
• Increases HDL-C
• Escalating dose titration to minimize side effects,
particularly flushing
Niacin
Adverse Effects
• Flushing
– Usually transient and improves with duration of
therapy
– ASA or NSAID prior to dosing may minimize
– Avoid ingestion of alcohol or hot drinks around time
of dosing
– If discontinued for an extended period, must escalate
and titrate dosing again
Niacin
Adverse Effects
• Transaminase elevation
• Rare cases of rhabdomyolysis with concomitant
HMG CoA reductase inhibitors
• Glucose intolerance
• Uric acid elevation
• Monitor anticoagulant therapy
• Use with caution in unstable angina/recovering
MI, especially with concomitant vasoactive drugs
Fibric Acid Derivatives
• Clofibrate (AtromidR), gemfibrozil (LopidR),
fenofibrate (TricorR)
• Decrease triglycerides, increase HDL-C levels
• Serum triglycerides > 1000 mg/dl associated with
significant risk of pancreatitis
• Not to be used to treat low HDL-C as only lipid
abnormality
• Increased incidence of non-coronary and ageadjusted all-cause mortality in studies (WHO)
Fibric Acid Derivatives
Adverse Effects
• Myalgias, myopathy, rhabdomyolysis
• Risk of rhabdomyolysis and acute renal failure
especially high with combined therapy with “statins”
• Cholelithiasis
• Transaminase elevation and Hgb/WBC depression
• Need to reduce anticoagulant dose
• Increased risk of liver and testicular malignancy
• Fetal toxicity
Family Approach to Treating
Hyperlipidemia and Reducing
Cardiovascular Risk
• Affected family members generally have same lipid
disorder
• Team Approach-Specialists from pediatrics, adult
medicine, and nutrition
• Programs are designed to fit into the family routine and
alter eating habits and physical activity
• Families develop an internal support structure which
improves compliance